Bakuchiol mitigates colitis through GPR120 activation

Abstract

Background

Sishen Wan (SSW) is a traditional herbal formula widely used in China to treat inflammatory bowel disease (IBD). However, effective compound(s) and the mechanism(s) of action remain mostly unelucidated.

Purpose

A demonstration study was carried out to identify the main components of SSW, investigate its effects, and explore the target mechanism in the treatment of IBD.

Study design and methods

The main chemical species of the SSW were identified using ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS/MS) method. The therapeutic effects of bakuchiol, the main component, were further analyzed in DSS-induced colitis mice. The target of bakuchiol was predicted using virtual screening and validated using pharmacological approaches. The possible mechanisms of bakuchiol were investigated using RNA-seq and bioassays with cytokines-induced human epithelial cell lines.

Results

Bakuchiol was identified as the main component of the SSW. Bakuchiol displayed therapeutic potential similar to SSW in alleviating body weight loss, disease activity index (DAI) increases, colonic shortening, colonic pathological injury and inhibiting proinflammatory genes Tnf-α, Il6, Il17a and Ifn-γ expression in mice with DSS-induced colitis. Compared with the clinical drug mesalazine, bakuchiol at lower doses showed a superior effect in alleviating body weight loss, DAI increases and colonic shortening. RNA-seq revealed that bakuchiol treatment suppresses inflammation pathways, such as chemokine signaling, IL-17 signaling and TNF signaling. Pharmacological profiling at a panel of GPCRs associated with IBD showed that bakuchiol was a GPR120 agonist with an EC₅₀ value of 37.80 ± 3.10 μM. In the TNF-α-induced HT-29 cells, we found that bakuchiol maintained the barrier function partially via the activation of GPR120.

Conclusion

This work demonstrates that bakuchiol is instrumental in SSW and provides evidence of the therapeutic effect of bakuchiol via activation of the GPR120 receptor, suggesting that bakuchiol may represent a novel potential agent for preventing and treating IBD.